9-fluoro-11beta,21-dihydroxy-16alpha,17-(2-propenylidenedioxy)-pregna-1,4-diene-3,20-dione and derivatives thereof

ABSTRACT

WHEREIN R: HYDROGEN ATOM OR ACYL RADICAL OF A SATURATED ALIPHATIC CARBOXYLIC ACID, CONTAINING FROM 2 TO 6 CARBON ATOMS AND EVENTUALLY SUBSTITUTED BY A FREE CARBOXYLIC GROUP (-COOH), OR BY A SALIFIED CARBOXYLIC GROUP SAID CATBOXYLIC GROUP BEING SEPARATED FROM THE -COGROUP OF THE ACYL RADICAL BY AT LEAST 2 CARBON ATOMS. THESE PRODUCTS ARE VERY USEFUL DRUGS MORE PARTICULARLY AS ANTIINFLAMMATORY DRUGS. THE PRODUCTS ARE PREPARED BY ACTION OF 9-FLUORO-11B16A,17,21- TETRAHYDROXY-PREGNA-1,4-DIENE-3,20-DIONE WITH 16A,17,21ACROLEIN IN THE PRESENCE OF AN ACID CATALYST, AND ISOLATION OF THE RESULTING 9-FLUORO-11B,21-DIHYDROXY-16A,17-(2-PROPENYLIDENEDIOXY)PREGNA-1,4-DIENE-3,20-DIONE, OR ESTERIFICATION OF SAID PRODUCT WITH THE ANHYDRID OF AN ACID OF FORMULA R&#39;&#39;-OH(R&#39;&#39;: ACYL RADICAL OF A SATURATED ALIPHATIC CARBOXYLIC ACID CONTAINING FROM 2 TO 6 CARBON ATOMS AND EVENTUALLY SUBSTITUTED BY A FRE CARBOXYLIC GROUP (-COOH)) AND EVENTUAL SALIFICATION BY AN ALKALINE AGENT.   21-(R-O-)PREGNA-1,4-DIENE   3,20-(O=),9-(F-),11-(HO-),16,17-(-O-CH(-CH=CH2)-),   PREGNAN DERIVATIVES OF THE GENERAL FORMULA:

United States Patent 3,798,216 9-FLUORO 115,21 DIHYDROXY-16a,17-(2-PRO-PENYLIDENEDIOXD-PREGNA 1,4-DIENE-3,20- DIONE AND DERIVATIVES THEREOFJacques Robert Boissier, Paris, and Roger-Ratouis, Saint ,Cloud, France,assignors to Societe Auonyme dite: Societe Industrielle pour laFabrication des Antibiotique (S.I.F.A. Puteaux, France No Drawing.Continuation of abandoned application Ser. ..No. '14,196, Feb. 25, 1970.This application May 8, 1972, Ser. No. 251,513 Int. Cl. C07c 173/00 US.'Cl. 2602 39.55 D 4 Claims AllSTRACT OF THE DISCLOSURE Pregnaiiderivative's'of the general formula:

' CHzOR wherein R: hydrogen atom or acyl radical of a saturatedaliphatic carboxylic acid, containing from 2 to 6 carbon atoms andeventually substituted by a free carboxylic group (COOH), or by asalified carboxylic group (-COOA: A being an alkaline metal or theammonium), said carboxylic group being separated from the CO- group ofthe acyl radical by at least 2 carbon atoms.

..These products are very useful drugs more particularly asantiinflammatory drugs.

The products are prepared by action of 9-fiuoro-1lfi- 16u;17,21tetrahydroXy-pregna-l,4-diene-3,20-dione with acrolein inihe presence ofan acid catalyst, and isolation of the resulting9-fluoro-1119,2l-dihydroxy-16u,17-(2-propenylidenedioxy)-pregna-1,4-diene-3,20-dione,or esterification" of said product'with the anhydrid of an acid offormula R'--OH [R: acyl radical of a saturated aliphatic carboxylic acidcontaining from 2 to 6 carbon atoms and eventually: substituted by afree carboxylic group COOH)] and eventual salification by an alkalineagent.

This is a continuation of application Ser. No. 14,196, filed Feb. 25,1970, now abandoned.

The present invention relates to new pregnan derivatives of the generalformula:

- e CHzOR 3,798,216 Patented Mar. 19, 1974 It is known that the termsacyl radical mean the univalent radical obtained by removing a hydroxylgroup from the carboxylic radical of the corresponding carboxylic acid.

The invention relates also to the process for the preparation of thederivatives of the Formula 1, process which comprises acetalizing the9-fluoro-11,6,l6a,17,2l-tetrahydroxypregna-l,4-diene-3,20-dione byacrolein in the presence of an acid catalyst, and isolating theresulting 9- fluoro ll,8,2l-dihydroxy-16u,17-(2-propenylidenedioxy)-pregna l,4-diene-3,20-dione, or esterifying said product with theanhydrid of an acid of formula R'OH, in which R represents the acylradical of a saturated aliphatic, linear or branched carboxylic acidcontaining from 2 to 6 carbon atoms and eventually substituted by a freecarboxylic group (COOH), said carboxylic group being separated from theCO group of the acyl radical by at least 2 carbon atoms, and eventually,when the R radical carries a free carboxylic group, salifying theobtained product by an alkaline agent.

Besides, the invention relates to the use of the derivatives of Formula1 as drugs and more particularly as antiinflam-matory drugs and to thepharmaceutical compositions comprising said derivatives as activesubstances.

The process for the preparation of the derivatives of Formula 1 ispreferably performed as follows:

(1) The acid catalyst is an inorganic acid such as hydrochloric orperchloric acid. The reaction is carried out in an organic solvent inerttowards the products in reaction, such as benzene, toluene, xylene,dioxan, tetrahydrofuran, with stirring, at room temperature and for 3 to24 hours; generally, said reaction is carried out during the timeallowing the 9 flnoro-l1/3,16a,17,2l-tetrahydroxy-pregna-1,4-diene-3,20-dione, in suspension at the beginning of the reaction, togo into solution. When the reaction is over, the acidity of the catalystis neutralized by treating the reaction mixture with an alkaline aqueoussolution, such as an aqueous soluiton of sodium bicarbonate, and the 9fiuoro 1lB,2l-dihydroxy-16a,17-(2-propenylidenedioxy)-pregna 1,4diene-3,20-dione is isolated by usual means such as extraction bysolvent, followed by purification and eventually recrystallization.

(2) The eventual esterification is carried out by adding the 9fiuoro-l1,8,21-dihydroxy-16a,17-(2-propenylidendioxy)-pregna-l,4-diene-3,20-dioneto a solution of the anhydride in pyridine, said anhydride being used inlarge excess in comparaison with the stoichiometric required quantity;the reaction is carried out at room temperature, for 10 to 40 hours.When the esterification is over, the reaction mixture is added to anaqueous acid solution and the resulting precipitate is isolated byfiltration.

(3) The eventual salification by an alkaline agent is realizedpreferentially by an alkaline or ammonium bicarbonate, carbonate orhydroxide. For example, it is possible to react the stoichiometricrequired quantity of an alkaline bicarbonate in aqueous solution with aderivative of Formula 1 carrying a free carboxylic (COOH), dissolved ina hydroorganic solution such as an aqueous solution of acetone. When thereaction is over, the resulting salt is isolated by elimination of thesolvent in vacuo.

The derivatives of Formula 1 have very interesting pharmacologicalproperties they have especially a very important thymolytic andglycogenic activity; they are remarkable antiinflammatory agents.

The derivatives of Formula 1 in which R represents a hydrogen atom(derivative designated hereafter as No. 2102-18 and described in ExampleNo. l), or the C0-CI-I radical (derivative designated hereafter as No.2102-26 and described in Example No. 2, or the COCH2'CHg-COOH(derivative designated hereafter as No. 2102-24 and described in ExampleNo. 3), or the COCH CH COONa (derivative designated hereafter as No.2102-25 and described in Example No. 4) were more particularly studied.Performed works and obtained results may be summarized as follows:

--(1) The thymolytic activity was evaluated on immature rats accordingto Stephensons Technique (J. Pharmacol. 1960, 12, 411-415). Thederivatives were injected by subcutaneous route, two times daily, one inthe morning and the other in the evening, for a period of three days.The animals were sacrificed on the fourth day. The thymi were removedand weighed. The results were expressed as mg. per 100 g. of bodyweight. The studies were performed on control animals and on animalsreceiving the doses of compounds as indicated in Table 1, in which thepercentage of thymic involution in treated animals was evaluated incomparison with the mean value of the thymus weight in control animals.

TABLE 1 Percentage of thymus invo lution related with administereddoses, twice a Solution or suspension in peanut oil. b Solubilized inwater extemporaneously by means of C OaHNa. c Aqueous solution.

(2) The activity of the derivatives on liver glycogen deposition in ratswas evaluated according to the technique of Venning et al.(Endocrinology, 1946, 38, 79). Groups of rats adrenalectomized sincefive days received subcutaneously, respectively a total dose of 2 meg.,4 meg. and 8 meg., for each animal, of derivative dissolved in 1.4 ml.of an aqueous solution containing whether 5% glucose-% ethanol (2102-18and 2102-26) or only 5% glucose (2102-25). This volume of 1.4 ml. ofsolution was given subcutaneously in 7 successive injections, at 45 min.intervals. The solvent was given in the same conditions to a controlgroup of rats. The average of liver glycogen is related in Table 2. Theresult obtained with control animals was practically 0.

TABLE 2 Average ofliver glycogen (as g. per 100 g. of organ), relatedwith administered doses, expressed as mcg./ rat (3) The antiinilammatoryactivity of the derivatives was evaluated on carrageenin abscess,according to a variant of the procedure of Benitz and Hall (Arch. Inter.Pharmacodyn. Therap. 1963, 144, 185-195), with the followingexperimental conditions: male rats weighing on about 50 g. were dividedinto groups of 5 animals. On the first day, the animals received, byoral or intraperitoneal route, whether the studied derivatives, or thealone vehicle. One-half of the daily dose was administered in themorning and the remainder in the evening.

On the second day, the same treatment was repeated and, immediatelyafter the first gavage, all the animals received cutaneously in thedorsal lumbar region 0.5 ml. of a 2% carrageenin suspension in saline.On the third day, 24 hours after the carrageenin injection, the animalswere sacrificed by chloroform inhalation. The dorsal skin was turnedback and the exudate and gelatinous material were collected and weighedtogether immediately.

The activity of the derivatives was expressed by the inhibitionpercentage of the abscess. This percentage was calculated by evaluatingthe difference between the weight of abscesses taken out of the controlanimals and of the treated animals and referring this diiference to theweight of the abscesses of the control animals.

The results appear in Table 3:

a Solution or suspension in an aqueous solution of gum arabic. b Aqueoussolution.

(4) Antiinflammatory activity of the derivatives was also evaluated oncarrageenin oedema according to Winter et al. (Proc. Soc. Exp. Biol.Med. 1962, 111, 544-547). The compounds were administered by oral routein aqueous solution (2102-25) or in gum arabic suspension (2102-18) tosuch a concentration that the ingested volume was 2.5 ml. per kg. ofbody weight. One hour after the gavage, the thickness of the right hindfoot was measured; then 0.05 ml. of a 1% carrageenin solution in salinewas injected in the foot-pad. Three hours later, the thickness of theinjected foot was again measured with a micrometer. The differencebetween the 2 measurements expressed the importance of the oedemainduced by the carrageenin. The measurements carried out in the sameconditions on control animals, receiving the vehicle alone, had allowedto evaluate the inhibition of swelling observed on the treated animals.The results are reported in Table 4:

TABLE 4 Inhibition percent of the carrageenin oedema related Owing totheir remarkable pharmacological properties, the derivatives of Formula1, according to the invention, are very useful drugs more particularlyas antiinflammatory drugs. They may be used in man, for example in actueor chronic rheumatic diseases, inflammatory dermatosis, asthma, viralhepatitis. The usual dose, variable according to the disease, theproduct used, the treated individal, and the route of administration,may be, for example, from 1 mg. to mg. per day by oral route in man.

In the derivatives of Formula 1, containing a salified carboxylic groupCOOA, when A represents an alkaline metal, it may be, for example,sodium or potassium.

As drugs, the derivatives of Formula 1 may be incorporated inpharmaceutical compositions for the digestive, parenteral or localroutes; these pharmaceutical compositions may be for example solid orliquid, and be realized in the pharmaceutical forms generally used inhuman medicine, such as tablets, coated tablets, capsules, granulatedsubstances, solutions, suspensions, syrups, suppositories, variedpreparations that can be injected such as solutions, suspensions,sterile powders to dissolve extemporaneously, pomades, creams, jellys,aerosols; they are prepared by the usual methods. The active principleor principles are incorporated therein with various excipients normallyemployed in these pharmaceutical compositions, for example, talcum, gumarabic, lactose, starch, magnesium stearate, cocoa butter, aqueous ornonaqueous' vehicles, animal or vegetal fats, paraffin derivatives,

'5 glycols, various wetting dispersing and emulsifying agents andpreservatives.

The following nonlimiting examples illustrate the invention:

I 9-fluoro-115,21-dihydroxy-16,17-(2-propenylideneidenedioxy)-pregna-1,4-diene-3 ,20-dione Analysis: C .,H FO Calculated (percent):C, 66.6; H, 6.8. Found (percent): C, 66.1; H, 6.7.

EXAMPLE 2 21 acetoxy-9-fluoro-1 1fl-hydroxy-16a,17(2-propenylidenedioxy)-pregna-1,4-dione-3,20-dione To a mixture of 1 ml. (0.0106 mole) ofacetic anhydried and 8 ml. of dry pyridine was added 1 g. (0.00231 mole)of9-fluoro-115,21-dihydroxy-1'6a,17-(2-propenylidenedioxy)-pregna-1,4-diene-3,20-dione.The resulting solution was left to stand for 20 hours, then was addeddropwise to a stirred mixture of 30 g. of ice and ml. of concentratedhydrochloric acid and the resulting mixture was stirred for 1 hour. Theobtained precipitate was filtered 011 and washed with water toneutrality. After vacuum-drying at 100 C. for 2 hours, 950 mg. (87%) of21-acetoxy-9-fluoro-11p-hydroxy-16u,17-(2-propcnylidenedioxy)-pregna-1,4-diene-3,20-dione, were obtained as white crystals, meltingpoint (vacuum sealed capillary tube): 22-0-222 C.

Analysis: C H FO Calculated (percent): C, 65.8; H, 6.6; F, 4.0. Found(percent): C, 66.0; H, 6.7; F, 4.0.

EXAMPLE 3 21 (3 carboxypropionyloxy)-9-fluoro-11f3-hydroxy-16a,

17 (2 propenylidenedioxy) pregna-1,4-diene,3,20- dione To a solution of10 g. (0.1 mole) of succinic anhydride in 42 ml. of dry pyridine wereadded portionwise 10 g. (0.0231 mole) of9-fluoro-1lfl,2l-dihydroxy-l6u,17-(2-propenylidenedioxy)-pregna-1,4-diene-3,20-dione. The resulting solutionwas left to stand for 20 hours, then was added dropwise to a stirredmixture of 160 g. of ice and 50 ml. of concentrated hydrochloric acidand the resulting mixture was stirred for 1 hour. The obtainedprecipitate was filtered ofi and washed with 1 l. of water. Theprecipitate was suspended in 1 l. of water, stirred for min., thenfiltered off. After vacuum drying at 45 C. for 24 hours, 10.4 g. (85%)of 21(3-carboxypropionyloxy)-9- fluoro-l 1fi-hydroxy-16m, 17-(2-propenylidenedioxy) pregna-1,4-diene-3,20dione were obtained as whitecrystals, melting point (open capillary tube): 148 C.

Sodium salt of 21-(3-carboxypropionyloxy) -9-fluoro -l lphydroxy 1611,17(2-propenylidenediqxy)-pregna-1,4- diene-3,20-dione To 20 ml. of waterwere added '10 g. (0.0188 mole) of 21 (3-carboxypropionyloxy)-9-fluoro-1lp-hydroxy-l6u, 17 (2propeuylidenedioxy)pregna-l,4-diene-3,20-dione dissolved in 65 m1.-ofacetone. To the resulting solution was added dropwise a solution of 1.58g. (0.0188 mole) of sodium bicarbonate in 40 ml. of water. The reactionmixture was stirred for 30 min., filtered, then the filtrate wasconcentrated in vacuo to dryness.-The' resulting-crystalline product wasdried at 45 C. in vacuo for 24 hours, to give- 10 g. (96%) of sodiumsalt of 21-(3-carboxypropionyloxy) 9fluoro-l1p-hydroxy-16a,17-(2-propenylidenedioxy)-pregna-1,4-diene-3,20-dioneas white, water soluble, crystals. Decompositionwithout melting above200 C. (open capillary tube).

EXAMPLE 5 Tablets were prepared which corresponded to the formula:

9-fluoro 11,3,21 dihydroxy-16a,17-(2-propeny1idenedioxy) pregna1,4-diene-3,20-dione Excipient sq. for a tablet 200 Norn.-Excipienttalcum, magnesium stearate.

lactose, starch,

EXAMPLE 6 A pomade was prepared which corresponded to the formula:

9-fluoro 115,21dihydroxy-16a,17-(2-propenylidenedioxy)-pregna-1,4-diene-3,20-dione 0.1Excipient sq. for 100 EXAMPLE 7 Parenteral suspensions were preparedwhich corresponded to the formula: 21-acetoxy 9 fluoro-llfihydroxy-16a,17-(2-propenylidenedioxy) pregna 1,4 diene 3,20- dione m 40Aqueous excipient sq. for ml 2 EXAMPLE 8 Parenteral preparations wereprepared which corresponded to the formula: 21-(3 carboxypropionyloxy) 9fiuoro-llB-hydroxy :,17 (2 propenylidenedioxy)-pregna-1,4-diene-3,20-dione mg 20 Alkaline aqueous excipient sq. for mL... 2

EXAMPLE 9 Tablets were prepared which corresponded to the fiormula:

Sodium salt of 21 (3 carboxypropionyloxy)-9- fiuoro 11 3 hydroxy 160:,17(2-propenylidenedioxy)-pregna-1,4-diene-3,20-dione Excipient sq. for atablet 200 starch, talcum,

NOTE.-Excipient magnesium stearate.

lactose,

pregna-1,4-diene-3,20-dione 'mg- 20 Aqueous excipient sq. for t. ml 2EXAMPLE-1L pornade was prepared which corresnondedl tothe formula: w r aExcipient sqtor i i I E M 2 .t .vEye-drons were prepared whichcorresponded to formula: 7

Sodium salt of 2-t(3 carboxypropionyloxy)-9-\fluoro- 11B hydroxy 160:,17(2-propenylidenedioxy)- pregna-l,4-diene 3;20 dione m'g .'.-10 Solutionisotonic with tears m1 10 -We claim:

A pregnan derivative havingthe formulaz.

CHaO R 8 in which R' .is amember selected from the group consisting of:I I (a) a hydrogen'atom,

(b) an acyl radical, of a saturated aliphatic carboxylic acid containingfrom 2 to 6 carbon atoms, and (c) an acyl radical of a substitutedstaturated aliphatic carboxylic acid containing from 2 to 6 carbon atomsin which the substitution in said carboxylic acid is a -COOA group inwhich A is a member of the group consisting of:.

(i) a hydrogen, (ii) an alkali metal, and (iii) an ammonium f said groupbeing separated from the -CO- group of 'th acyl radical by at least 2carbon atomsn "2; A pregnan derivative according to claim 1, wherein Rrepresentsa hydrogen atom; A pregnan derivative according to claim 1,wherein R represents the radical -'-'-CO--CH 4. A pregnan derivativeaccording to claim 1, wherein R is a member selected from the groupconsisting of (a) C OCH -CH COOH and (b OO- CHfCH CCONa radicals.

References Cited UNITED STATES PATENTS 3,048,581 8/1962 'Fried 260-239553,053,836 9/1962 Fried 260-23955 3,126,375 3/1964 Ringold et a1.260239.55 $180,797 4/1965 Cacchillo'et a1. 167-77 HENRY A. FRENCH,Primary Examiner US. Cl. X.R. 424241 UNITED STATES PATENT OFFICECERTIFICATE OF QQRECHQ Patent No. 3,798,216 Dated 19 March 1974Inventor(s) Jacques R. Boissier and Roger Ratouis It is certified thaterror appears in the above-identified patent and that said LettersPatent are hereby corrected as shown below:

Cole 1, line 10, insert which claims the priority of French ApplicationsNumbers 69 06348 filed March 7, 1969 and 69 38912 filed November 13,1969 between "1970" and the period (a) and Col. 1, line 51, insert whichclaims the priority of French Applications Numbers 69 06348 filed March7, 1969 and 69 38912 filed November 13, 1969 between "now abandoned" andthe period 0 Signed and sale this third Day of February 1976 [SEAL]Arrest:

RUTl-l C. MASON C. MARSHALL DANN Arresting Officer CommissionerufParents and Trademarks P -w UNITED STATES PATENT OFFICE CERTIFICATE OFCORRECTION Pat nt 3.798.2l- Dated March 19. 1974 lnventofl Jacques R.Boiesier et al it; is certified that error appears in theabove-identified patent and that said Letters Patent are herebycorrected as shown below:

Col. 3, line 36 and 37 -change "2 megQ, 4. meg. and 8 meg.

to --2 mcg, 4 mcg and 8 mcg',

Col. 3, line 70 change -"cutaneou sly to --s 'xibcutaneously- Col. 5,linev 6" and (first angiv eec qnd, line Example 1) change"9-fluoro-llB,2l--dihydroxy--l6cx,l7-(2-propenylideneidenedioxy)-pregna-l;4+diene3,20-dione"to --9f1uoro-ll6,2l-dihydroxy-l6oa,17 (2-propenylidenedioxy)-pregnal,4diene3,20-dione- Col. 5, line 32 change "dried" to-drid- Signed and sealed this 17th day bf December 1974.

(SEAL) Attest: MECOY' 14. GIBSON JR. MARSHALL'DANN Attesting Officer vCommissioner of Patents UNITED STATES PATENT OFFICE CERTIFICATE OFCORRECTION Patent No. 3,798,216 Dated March 19; 1974' Inventor(s)JACQUES ROBERT BOISSIER, ET. AL.

It is certified that error appears in the above-identified patent andthat said Letters Patent are hereby corrected as shown below:

Column 1, lines 2-4 should read as follomsz 9 -F1uoro 11B,21-dihydroxy-16a,17-(2-propenylidenedioxy)-pregnal,4-

diene-3,20dione and derivatives thereof Column 1, lines 6, 7 and 8,"Societe Industrielle pour la Fabrication des Antibiotique'(S.I.F.A.),Puteaux, France" should read Roussel-Uclaf; Paris, France, a company ofFrance Signed and sealed this 13th day of August 1974.

(SEAL) Attest 2 MCCOY M. GIBSON, JR C MARSHALL DANN Attesting OfficerCommissioner of Patents 4 FORM po'wso (m'sg) USCOMM-DC 60376-P69 U.S.GOYERNMENT PRINTING OFFICE ISQ 0-366-33l,

